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1.11.4 α-adrenoreceptor agonists.
Agents that can stimulate α-andrenoceptors modulate a variety of physiological
processes including the reduction of blood pressure, sedation and the inhibition of
intestinal fluid secretion. 108 Scientists at Allergan Pharmaceuticals targeted the α –
andrenoceptor to reduce intraocular pressure(IOP), a common condition in patients
suffering from glaucoma. 109 The challenge in designing such agents stems from the
ability of α –andrenoceptor subtypes to modulate different biological processes, most
concerning are those in the central nervous system (CNS). One approach to
minimizing CNS effect is topical application, minimizing access of the compound to
the CNS. From the known α-andrenoceptor agonist clonidine, 110 modifications to
minimize CNS access generated the lead compounds p-aminoclonidine and AGN-
191103 (21) (Fig. 1.13.4). The The alternative approach is to discover compounds
displaying enough selectivity between the α-andrenoceptor subtypes such that they
exhibit an enhanced therapeutic index. This led to replacing the imidazolidin-imine
with a 2-aminoimidazole. This compound (a) was selected for further evaluation.
Binding assays demonstrated (a) bound to the α2A-receptor with a Ki = 1.7 nM and
was 1200-fold selective for the α2A –receptor over the α1-receptor, 50-fold selective
for the α2A –receptor over the α2B –receptor, and 10-fold selective for the α2A –
receptor over the α2C –receptor. Compound (a) was found to be effective in vivo with
an EC50 = 8.7 nM and importantly remained effective when administered
intravenously, demonstrating its capability of crossing the blood-brain barrier.
H
N N
NH
Cl
Cl
H
N N
NH
Cl
Cl
NH 2
Clonidine p-aminoclonidine AGN-191103
Fig.- 1.11.4 α-adrenoreceptor agonists.
H
N
NH
N
N
N
H
N
N
H
N
O
O
Compound (a)
1.11.5 Anti Cancer Activity
Cancer has been the leading cause of death worldwide. Chemotherapy remains one of
the major treatment options available for cancer, andmost of the currently used
anticancer drugs are administered to patients via a parenteral infusion or bolus
injection. Clinical complications with the parenteral administrations have been